Lipoprotein lipase (LPL), and to some degree hepatic lipase (HL), have been associated with phenotypes comprising the metabolic syndrome, including insulin resistance, hypertension, obesity, elevated plasma triglyceride levels, and low HDL cholesterol concentrations. This Project will use multifaceted approaches to identify both cis- and trans-acting factors influencing lipase activity levels, and the association of these factors with the metabolic syndrome. The first two aims will identify proteins that assist nascent forms of LPL and HL to fold into fully functional enzymes, and assess the ability of these proteins to regulate lipase activity levels. The third aim will determine mechanisms responsible for the interaction of LPL with its chief modulator of activity, apoC-ll, and the location of heparin binding sites that correctly orient LPL at the cell surface. The fourth specific aim will determine whether variation in the 3'-untranslated region of the LPL gene is responsible for the association of linked genetic markers with measures of insulin sensitivity. The final aim will elucidate the role of selected candidate genes in controlling the levels of post-heparin LPL activity. Thus, this Project collectively investigates a constellation of diverse factors influencing lipase activity levels, a possible key determinant of many abnormalities underlying the metabolic syndrome.